{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T16:59:30Z","timestamp":1773075570866,"version":"3.50.1"},"reference-count":43,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,10,6]],"date-time":"2022-10-06T00:00:00Z","timestamp":1665014400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>C-reactive protein (CRP) has been shown to be a potential candidate target in the immunotherapy of severe influenza A infection. However, it is unclear on the pathogenesis associated with CRP in influenza infections. Here, we used influenza A H1N1 CA04 to infect human CRP transgenic mice (KI), CRP knockout mice (KO), and wild-type mice (WT), respectively, and compared the viral pathogenicity and associated immune response in those mice. The results showed that CA04 infection resulted in 100%, 80%, and 60% death in KO, KI, and WT mice, respectively. Compared to WT mice, CA04 infection resulted in higher TCID50 in lungs on day 3 after infection but lowered HI antibody titers in sera of survivors on day 21 after infection in KI mice. ELISA assay showed that IFN-<jats:bold>\u03b3<\/jats:bold>concentration was significantly increased in sera of WT, KI, or KO mice on day 7 after infection, and IL-17 was remarkably increased in sera of WT mice but decreased in sera of KI mice while no significant change in sera of KO mice on day 3 or 7 after infection. Quantitative RT-PCR showed that the relative expression levels of immune checkpoint CTLA-4, LAIR-1, GITR, BTLA, TIM-3, or PD-1 mRNA in the lung presented decreased levels on day 3 or 7 after infection in KI or KO mice. The correlation analysis showed that mRNA expression levels of the 6 molecules positively correlated with viral TICD50 in WT mice but negatively correlated with viral TCID50 in KI or KO mice. However, only LAIR-1 presented a significant correlation in each lung tissue of WT, KI, or KO mice with CA07 infection statistically. IHC results showed that LAIR-1 positive cells could be found in WT, KO, or KI mice lung tissues with CA04 infection, and the positive cells were mainly distributed in an inflammatory dense area. Our results suggested that deficiency of CRP or human CRP<jats:bold>t<\/jats:bold>ransgenic treatment aggravates influenza A virus infection in mice. CRP is a double sword in immune regulation of influenza infection in which IL-17 and immune checkpoint may be involved.<\/jats:p>","DOI":"10.3389\/fimmu.2022.1028458","type":"journal-article","created":{"date-parts":[[2022,10,6]],"date-time":"2022-10-06T04:35:39Z","timestamp":1665030939000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Deficiency of C-reactive protein or human C-reactive protein transgenic treatment aggravates influenza A infection in mice"],"prefix":"10.3389","volume":"13","author":[{"given":"Zhuohan","family":"Zhang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yongjun","family":"Gao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Li","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Junhao","family":"Luo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rongbao","family":"Gao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,10,6]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"487","DOI":"10.1055\/s-0036-1584801","article-title":"Human influenza virus infections","volume":"37","author":"Peteranderl","year":"2016","journal-title":"Semin Respir Crit Care Med"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(17)33293-2","article-title":"Estimates of global seasonal influenza-associated respiratory mortality: a modelling study","volume":"391","author":"Iuliano","year":"2018","journal-title":"Lancet"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1038\/s41579-021-00542-7","article-title":"Influenza virus and SARS-CoV-2: pathogenesis and host responses in the respiratory tract","volume":"19","author":"Flerlage","year":"2021","journal-title":"Nat Rev Microbiol"},{"key":"B4","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1016\/j.ajpath.2011.03.013","article-title":"Excessive neutrophils and neutrophil extracellular traps contribute to acute lung injury of influenza pneumonitis","volume":"179","author":"Narasaraju","year":"2011","journal-title":"Am J Pathol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.00943","article-title":"Evolution of c-reactive protein","volume":"10","author":"Pathak","year":"2019","journal-title":"Front Immunol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/S0161-5890(01)00042-6","article-title":"Human c-reactive protein: expression, structure, and function","volume":"38","author":"Volanakis","year":"2001","journal-title":"Mol Immunol"},{"key":"B7","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1111\/j.1749-6632.1982.tb22124.x","article-title":"The phenomenon of the acute phase response","volume":"389","author":"Kushner","year":"1982","journal-title":"Ann NY Acad Sci"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2017.07.010","article-title":"C-reactive protein mediating immunopathological lesions: A potential treatment option for severe influenza a diseases","volume":"22","author":"Gao","year":"2017","journal-title":"EBioMedicine"},{"key":"B9","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1016\/j.jcmgh.2021.09.003","article-title":"C-reactive protein protects against acetaminophen-induced liver injury by preventing complement overactivation","volume":"13","author":"Li","year":"2022","journal-title":"Cell Mol Gastroenterol Hepatol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1172\/JCI200318921","article-title":"C-reactive protein: a critical update","volume":"111","author":"Pepys","year":"2003","journal-title":"J Clin Invest"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of relative gene expression data using real-time quantitative PCR and the 2(-delta delta C(T)) method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"},{"key":"B12","first-page":"71","article-title":"An improvement of the 2^(-delta delta CT) method for quantitative real-time polymerase chain reaction data analysis","volume":"3","author":"Rao","year":"2013","journal-title":"Biostat Bioinforma Biomath"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1080\/22221751.2022.2071175","article-title":"Virus-host interaction networks as new antiviral drug targets for IAV and SARS-CoV-2","volume":"11","author":"Chen","year":"2022","journal-title":"Emerg Microbes Infect"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1001002","article-title":"CCR2-antagonist prophylaxis reduces pulmonary immune pathology and markedly improves survival during influenza infection","volume":"186","author":"Lin","year":"2011","journal-title":"J Immunol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.115.306656","article-title":"From c-reactive protein to interleukin-6 to interleukin-1: Moving upstream to identify novel targets for atheroprotection","volume":"118","author":"Ridker","year":"2016","journal-title":"Circ Res"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2013.09.004","article-title":"Targeting interleukin-6 in inflammatory autoimmune diseases and cancers","volume":"141","author":"Yao","year":"2014","journal-title":"Pharmacol Ther"},{"key":"B17","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1007\/s00011-018-1188-x","article-title":"C-reactive protein as a biomarker of severe H1N1 influenza","volume":"68","author":"Vasileva","year":"2019","journal-title":"Inflammation Res"},{"key":"B18","doi-asserted-by":"publisher","first-page":"288","DOI":"10.1186\/1471-2334-10-288","article-title":"C-reactive protein serum levels as an early predictor of outcome in patients with pandemic H1N1 influenza a virus infection","volume":"10","author":"Zimmerman","year":"2010","journal-title":"BMC Infect Dis"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1002\/j.1460-2075.1987.tb02745.x","article-title":"Inducible and tissue-specific expression of human c-reactive protein in transgenic mice","volume":"6","author":"Ciliberto","year":"1987","journal-title":"EMBO J"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.03058-14","article-title":"C-reactive protein protects mice against pneumococcal infection via both phosphocholine-dependent and phosphocholine-independent mechanisms","volume":"83","author":"Gang","year":"2015","journal-title":"Infect Immun"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1111\/imm.12266","article-title":"C-reactive protein is essential for innate resistance to pneumococcal infection","volume":"142","author":"Simons","year":"2014","journal-title":"Immunology"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.176.7.4369","article-title":"Role of the property of c-reactive protein to activate the classical pathway of complement in protecting mice from pneumococcal infection","volume":"176","author":"Suresh","year":"2006","journal-title":"J Immunol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.178.2.1158","article-title":"Human c-reactive protein protects mice from streptococcus pneumoniae infection without binding to pneumococcal c-polysaccharide","volume":"178","author":"Suresh","year":"2007","journal-title":"J Immunol"},{"key":"B24","doi-asserted-by":"crossref","DOI":"10.4049\/jimmunol.155.5.2557","article-title":"Human c-reactive protein is protective against fatal streptococcus pneumoniae infection in transgenic mice","volume":"155","author":"Szalai","year":"1995","journal-title":"J Immunol"},{"key":"B25","doi-asserted-by":"crossref","DOI":"10.4049\/jimmunol.128.5.2374","article-title":"Human c-reactive protein is protective against fatal streptococcus pneumoniae infection in mice","volume":"128","author":"Yother","year":"1982","journal-title":"J Immunol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciu053","article-title":"Comparison of patients hospitalized with influenza a subtypes H7N9, H5N1, and 2009 pandemic H1N1","volume":"58","author":"Wang","year":"2014","journal-title":"Clin Infect Dis"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijid.2020.05.055","article-title":"Association of inflammatory markers with the severity of COVID-19: A meta-analysis","volume":"96","author":"Zeng","year":"2020","journal-title":"Int J Infect Dis"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijid.2021.05.057","article-title":"SAA and CRP are potential indicators in distinction and severity assessment for children with influenza","volume":"108","author":"Zou","year":"2021","journal-title":"Int J Infect Dis"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1007\/s00281-016-0558-0","article-title":"The host immune response in respiratory virus infection: balancing virus clearance and immunopathology","volume":"38","author":"Newton","year":"2016","journal-title":"Semin Immunopathol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1111\/resp.14141","article-title":"IL-17A is a common and critical driver of impaired lung function and immunopathology induced by influenza virus, rhinovirus and respiratory syncytial virus","volume":"26","author":"Liu","year":"2021","journal-title":"Respirology"},{"key":"B31","doi-asserted-by":"publisher","first-page":"396","DOI":"10.1016\/j.jmii.2019.07.009","article-title":"Anti-IFN-gamma therapy alleviates acute lung injury induced by severe influenza a (H1N1) pdm09 infection in mice","volume":"54","author":"Liu","year":"2021","journal-title":"J Microbiol Immunol Infect"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01234-17","article-title":"Novel role for interleukin-17 in enhancing type 1 helper T cell immunity in the female genital tract following mucosal herpes simplex virus 2 vaccination","volume":"91","author":"Bagri","year":"2017","journal-title":"J Virol"},{"key":"B33","doi-asserted-by":"publisher","first-page":"190109","DOI":"10.1098\/rsob.190109","article-title":"The protective and pathogenic roles of IL-17 in viral infections: friend or foe","volume":"9","author":"Ma","year":"2019","journal-title":"Open Biol"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1005367","article-title":"IL-17A promotes pulmonary b-1a cell differentiation via induction of blimp-1 expression during influenza virus infection","volume":"12","author":"Wang","year":"2016","journal-title":"PLoS Pathog"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-immunol-032414-112049","article-title":"Coinhibitory pathways in immunotherapy for cancer","volume":"34","author":"Baumeister","year":"2016","journal-title":"Annu Rev Immunol"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1038\/nrc3239","article-title":"The blockade of immune checkpoints in cancer immunotherapy","volume":"12","author":"Pardoll","year":"2012","journal-title":"Nat Rev Cancer"},{"key":"B37","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1038\/nri.2017.112","article-title":"Immune checkpoint blockade in infectious diseases","volume":"18","author":"Wykes","year":"2018","journal-title":"Nat Rev Immunol"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1102044","article-title":"Leukocyte-associated ig-like receptor-1-deficient mice have an altered immune cell phenotype","volume":"188","author":"Tang","year":"2012","journal-title":"J Immunol"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1183\/13993003.01805-2016","article-title":"The instructive extracellular matrix of the lung: basic composition and alterations in chronic lung disease","volume":"50","author":"Burgstaller","year":"2017","journal-title":"Eur Respir J"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.00842","article-title":"LAIR-1 limits neutrophilic airway inflammation","volume":"10","author":"Kumawat","year":"2019","journal-title":"Front Immunol"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1126\/science.271.5246.173","article-title":"Immunology taught by viruses","volume":"271","author":"Zinkernagel","year":"1996","journal-title":"Science"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.01777","article-title":"Alveolar macrophages in the resolution of inflammation, tissue repair, and tolerance to infection","volume":"9","author":"Allard","year":"2018","journal-title":"Front Immunol"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.3109\/08916934.2012.748752","article-title":"Balancing immunity and autoimmunity","volume":"46","author":"Incorvaia","year":"2013","journal-title":"Autoimmunity"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.1028458\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,2,22]],"date-time":"2023-02-22T04:14:05Z","timestamp":1677039245000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.1028458\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,10,6]]},"references-count":43,"alternative-id":["10.3389\/fimmu.2022.1028458"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2022.1028458","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,10,6]]},"article-number":"1028458"}}